Phenyl-quinolizidines

ABSTRACT

Phenyl-quinolizidines of the formula ##STR1## wherein X, Y, R 1  and R 2  are as hereinafter set forth, are described. The compounds of formula I are useful as antipsychotics, antiemetics and analgesics.

BRIEF SUMMARY OF THE INVENTION

The invention relates to phenyl-quinolizidines characterized by theformula ##STR2## wherein X, Y, R¹ and R² are as described below: X ishydrogen, fluorine, chlorine, lower alkoxy, lower alkyl ortrifluoromethyl; Y is hydrogen, fluorine, chlorine, lower alkoxy orlower alkyl, preferably hydrogen; R¹ is hydroxy, lower alkoxy, acyloxyor, when R² is the group A defined hereinafter, hydrogen; and R² islower alkyl, phenyl optionally substituted by halogen, lower alkoxy ortrifluoromethyl, or when R¹ is hydrogen, a group A of the formula##STR3## wherein R³, R⁴, R⁵ and R⁶ are as described below: R³ is oxygenor sulfur; R⁴ is hydrogen or lower alkyl; R⁵ and R⁶ independently arehydrogen, methyl, fluorine, chlorine, methoxy or trifluoromethyl, ortaken together are --(CH₂)₄ --,

as the racemates or the enantiomers, as well as the free bases and theacid addition salts thereof.

DETAILED DESCRIPTION OF THE INVENTION

The phenyl-quinolizidines of the invention are characterized by theformula ##STR4## wherein X, Y, R¹ and R² are as described below: X ishydrogen, fluorine, chlorine, lower alkoxy, lower alkyl ortrifluoromethyl; Y is hydrogen, fluorine, chlorine, lower alkoxy orlower alkyl, preferably hydrogen; R¹ is hydroxy, lower alkoxy, acyloxyor, when R² is the group A defined hereinafter, hydrogen; and R² islower alkyl, phenyl optionally substituted by halogen, lower alkoxy ortrifluoromethyl, or, when R¹ is hydrogen, a group A of the formula##STR5## wherein R³, R⁴, R⁵ and R⁶ are as described below: R³ is oxygenor sulfur; R⁴ is hydrogen or lower alkyl; R⁵ and R⁶ independently, arehydrogen, methyl, fluorine, chlorine, methoxy or trifluoromethyl, ortaken together, are --(CH₂)₄ --,

in the form of their racemates or their enantiomers, as well as in theform of the free bases or in the form of the acid addition salts.

As shown in formula I and in various of the other formulas, the hydrogenatoms in the 7- and 9a-positions are in trans relationship to oneanother, whereby in the formulas the hydrogen atom in the 9a-position isarbitrarily shown in the β-position and the hydrogen atom in the7-position is correspondingly shown in the α-position. The relativeconfiguration shown for the phenyl-quinolizidines of formula I of theinvention as well as the corresponding intermediates and startingmaterials is not intended to exclude, and in fact embraces, thecorresponding enantiomeric forms, namely, compounds having hydrogenatoms in the 9a α- and 7β-positions, as well as the racemates of thesetwo enantiomeric forms. Similarly, with reference to the configurationin the 2-position of the phenyl-quinolizidines, it is not intended toexclude the racemates or enantiomers. Thus, for example, in formula IIIhereinafter, the hydrogen atoms in the 2- and 9a-positions are shown inthe β-position and the hydrogen atom in the 7-position is shown in theα-position, then accordingly the relative configuration at these threeasymmetric centers is specified (9aH to 7H: trans; 9aH to 2H: cis), butthe absolute configuration is not specified and either enantiomer isintended.

The lower alkyl and lower alkoxy groups referred to herein are alkyl andalkoxy groups, respectively, which contain 1-6, preferably 1-4, carbonatoms, the groups containing 3 and more carbon atoms beingstraight-chain or branched-chain. An acyloxy group referred to as apossible R¹ -substituent can be derived from an organic, saturated orunsaturated, optionally substituted carboxylic acid, preferably anoptionally halogen-substituted lower alkanecarboxylic acid, such asacetic acid, trifluoroacetic acid or the like.

As acid addition salts of the phenyl-quinolizidines of the inventionthere come into consideration pharmacologically compatible salts withthe organic and inorganic acids customarily used for salt formation.Examples of such acids are mineral acids, for example, sulfuric acid,nitric acid, phosphoric acid and hydrohalic acids, such as hydrochloricacid and hydrobromic acid, and organic acids, for example, tartaricacid, citric acid, aliphatic or aromatic sulfonic acids, maleic acid,mandelic acid, and the like. The salt formation can be carried out in aknown manner.

It is noted that the compounds of formula I embrace the followingsub-groups:

(a) alkyl- or aryl-carbinols of the formula ##STR6## preferably those ofthe formula ##STR7## wherein X, Y and R² are as previously described, inracemic form and in the form of the enantiomers, as well as, if desired,in the form of acid addition salts,

(b) the esters and ethers of the carbinols set forth under (a), that is,the compounds of the formula ##STR8## wherein X, Y and R² are aspreviously described, and R⁷ is lower alkyl or acyl, in racemic form andin the form of the enantiomers, as well as, if desired, in the form ofacid addition salts,

(c) the benzimidazoline and benzimidazolinethione derivatives of theformula ##STR9## wherein X, Y, R³, R⁴, R⁵ and R⁶ are as previouslydescribed, in racemic form and in the form of the enantiomers, as wellas, if desired, in the form of acid addition salts, and

(d) the methylbenzimidazole derivatives of the formula ##STR10##

wherein X, Y, R⁵ and R⁶ are as previously described, in racemic form andin the form of the enantiomers, as well as, if desired, in the form ofacid addition salts.

The compounds of formula II hereinbefore have predominantly neurolepticactivity. Preferred amongst these are the compounds of formula II-1hereinbefore, in particular those in which R² is branched-chain loweralkyl, X is fluorine or chlorine and Y is hydrogen, fluorine orchlorine, X and Y are present in the ortho- and/or para-position,predominantly because of their neuroleptic activity. Especiallypreferred compounds of formula II-1 are those wherein R² is tert.butyl,X is o-chloro and Y is p-chloro or R² is tert.butyl, X isp-trifluoromethyl and Y is hydrogen.

The compounds of formula IV hereinbefore are preferred predominantlybecause of their analgesic activity. Especially preferred compounds offormula IV are those in which

(a) X and Y are hydrogen, OR⁷ is acetoxy and has the same orientation asthe 9a-hydrogen and R² is n-butyl,

(b) X and Y are hydrogen, OR⁷ is trifluoroacetoxy and has the sameorientation as the 9a-hydrogen atom and R² is tert.butyl, or

(c) X is o-chloro, R² is phenyl and has the same orientation as the9a-hydrogen atom and OR⁷ represents acetoxy.

The compounds of formulas III-1 and III-2 hereinbefore havepredominantly neuroleptic activity. The benzimidazolinone andbenzimidazolinethione derivatives of formula III-1 in which X ishydrogen, o-fluoro or o-chloro, Y is hydrogen, R³ is oxygen or sulfur,R⁴ is hydrogen, R⁵ is fluorine, chlorine or trifluoromethyl and R⁶ ishydrogen, chlorine or fluorine are preferred. The following compounds offormula III-1 are especially preferred:

(a) X=o-Cl; Y,R⁴,R⁵,R⁶ =H; R³ =O,

(b) X=o-Cl; Y,R⁴ =H; R³ =O; R⁵,R⁶ =CH₃,

(c) X=o-Cl; Y,R⁴ =H; R³ =O; R⁵,R⁶ =Cl,

(d) X=o-Cl; Y,R⁵,R⁶ =H; R³ =O; R⁴ =CH₃,

(e) X=o-Cl; Y,R⁴,R⁶ =H; R⁵ =CF₃ ; R³ =O,

(f) X=o-Cl; Y,R⁴,R⁶ =H; R⁵ =Cl; R³ =O,

(g) X=o-Cl; Y,R⁴,R⁶ =H; R⁵ =Cl; R³ =S,

(h) X=o-Cl; Y,R⁴ =H; R³ =S,R⁵,R⁶ =Cl,

(i) X=o-Cl; Y,R⁴ =H; R³ =O; R⁵ and R⁶ together=--(CH₂)₄ --,

(j) X=o-F; Y,R⁴ =H; R³ =O; R⁵,R⁶ =CH₃,

(k) X=o-F; Y,R⁴ =H; R³ =O; R⁵,R⁶ =Cl,

(l) X=o-F; Y,R⁴ =H; R³ =S; R⁵,R⁶ =Cl,

(m) X=o-F; Y,R⁴ =H; R³ =O; R⁵ and R⁶ together=--(CH₂)₄ --,

(n) X=o-F; Y,R⁴,R⁶ =H; R⁵ =CF₃ ; R³ =O,

(o) X=o-F; Y,R⁴,R⁶ =H; R⁵ =CF₃ ; R³ =S,

(p) X=o-F; Y,R⁴,R⁶ =H; R⁵ =Cl; R³ =O,

(q) X=o-F; Y,R⁴,R⁶ =H; R⁵ =Cl; R³ =S.

In accordance with the process of the invention, thephenyl-quinolizidines aforesaid are prepared by

(1) for the preparation of compounds of the formula ##STR11## wherein X,Y and R² are as previously described, either (a) reacting a ketone ofthe formula ##STR12## wherein X and Y are as previously described, witha metal-organic compound yielding the group R² and, if desired,separating the mixture of diastereomers obtained, or (b) adding water atthe Δ¹ - or Δ² -double bond present in a compound of the formula##STR13## wherein X, Y and R² are as previously described, and thebroken line denotes a double-bond in the 1,2- or 2,3-position, byreaction with a hydrating agent, or

(2) for the preparation of compounds of the formula ##STR14## wherein X,Y and A are as previously described, reacting a compound of the formula##STR15## wherein X and Y are as previously described, and Z is acleavable group, with a compound of the formula

    H--A                                                       VIII

wherein A is as previously described, or

(3) for the preparation of a compound of the formula ##STR16## wherein Xand Y are as previously described and A' has any of the values accordedto A hereinbefore except that R³ is oxygen, catalytically hydrogenatinga compound of the formula ##STR17## wherein X, Y and A' are aspreviously described, or

(4) for the preparation of a compound of the formula ##STR18## wherein Xand Y are as previously described and A" has any of the values accordedto A hereinbefore with the exception that R³ is oxygen and R⁴ ishydrogen, condensing a phenylenediamine of the formula ##STR19## whereinX, Y, R⁵ and R⁶ are as previously described, with a cyclizing agent ofthe formula ##STR20## wherein R^(b) and R^(c) are halogen, amino or1-imidazolyl, or with acetic acid or an orthoacetic acid ester, or

(5) for the preparation of a compound of the formula ##STR21## whereinX, Y, R⁴, R⁵ and R⁶ are as previously described, either (a) reacting acorresponding oxo compound of the formula ##STR22## wherein X, Y, R⁴, R⁵and R⁶ are as previously described, with phosphorus pentasulfide, or (b)reacting a phenylene-diamine of formula X hereinbefore withthiophosgene, thiocarbonyldiimidazole or carbon disulfide and, ifdesired, N-alkylating the reaction product, or

(6) for the preparation of compounds of the formula ##STR23## wherein X,Y, R³, R⁵ and R⁶ are as previously described and R⁴¹ is lower alkyl,N-alkylating a compound of the formula ##STR24## wherein X, Y, R³, R⁵and R⁶ are as previously described, or

(7) for the preparation of ethers and esters of the formula ##STR25##wherein X, Y, R² and R⁷ are as previously described, reacting an alcoholof formula II hereinbefore with an etherifying or esterifying agentyielding the group R⁷ and, if desired, cleaving a racemate obtained and,also if desired, converting a base obtained into an acid addition salt.

All of the reactions specified in the aforementioned process embodiments(1) to (7) can be carried out according to known methods.

For the conversion of a ketone of formula V into a tertiary carbinol offormula II in accordance with process embodiment (1) (a) there can beused the customary metal-organic compounds yielding the group R² such asthe corresponding Grignard compounds of the formula R² -Mg-halogen, R²-lithium compounds or R² -lithium-copper compounds.

A third asymmetric center (in the 2-position) occurs when a carbinol isprepared from a ketone of formula V. The newly introduced group R² canin this case occupy the cis- and/or trans-position in relation to the9a-hydrogen atom. Thus, for example, from a racemic ketone of formula Vthere are obtained as described in Example 3 hereinafter twodiastereomeric carbinols of formula II, each as the racemate, while froma racemic ketone of formula V there is obtained, as described in Example1 hereinafter, of the two theoretically possible diastereomericracemates of formula II, practically only the one racemate, namely, thatin which R² is in the trans-position to the 9a-hydrogen atom, whichcompound is characterized by formula II-1.

Diastereomeric mixtures obtained as well as racemates obtained can beseparated or cleaved according to known methods.

Water at the Δ¹ - or Δ² -double bond of a compound of formula VI can beadded, in accordance with process embodiment (1) (b) using as thehydrating agent, for example, aqueous sulfuric acid.

For the preparation of benzimidazole derivatives of formula III, inaccordance with process embodiment (2), a compound of formula VII whichcontains, for example, a chlorine or bromine atom or a mesyloxy ortosyloxy group as the cleavable group can be reacted with a compound offormula VIII, preferably in the form of an alkali metal salt.

For the preparation of the benzimidazole derivatives of formula III-3according to process embodiment (3), the Δ¹ -double bond present in acompound of formula IX can be catalytically hydrogenated. As thecatalyst, there can be used a customary hydrogenation catalyst, such asplatinum oxide, palladium/carbon, for example, 10%, or the like.

For the preparation of the benzimidazole derivatives of formula III-4according to process embodiment (4), a phenylene-diamine of formula Xcan be reacted with a cyclizing agent of formula XI, for example,phosgene, carbonyldiimidazole, urea, or the like, to give abenzimidazolinone derivative of formula III-1 or with acetic acid or anorthoacetic acid ester, for example, the trimethyl or triethyl ester, togive a methylbenzimidazole derivative of formula III-2.

For the preparation of the thiones of formula III-3, in accordance withprocess embodiment (5) (a), the oxygen atom present in the imidazolering of an oxo compound of formula III-6 can be replaced by a sulfuratom using phosphorus pentasulfide in accordance with known methods, orin accordance with process embodiment (5) (b), a phenylene-diamine offormula X can be reacted with thiophosgene, thiocarbonyldiimidazole orcarbon disulfide in a known manner. The subsequent, optionalN-alkylation at R⁴ is effected in an analogous manner to that describedhereinafter in connection with process embodiment (6).

Embodiments (4) and (5) (b) are especially well suited to thepreparation of compounds of formula III-4 or III-5 in which R⁵ isdifferent from R⁶.

For the preparation of compounds III-7 which are N-alkylated in theimidazole ring according to process embodiment (6), there can be used acustomary N-alkylating agent, such as a lower alkyl halide, for example,methyl iodide.

For the preparation of the ethers and esters of formula IV according toprocess embodiment (7), a carbinol of formula II can be esterified in aknown manner, for example, by reaction with an acid anhydride of theformula (R⁷ CO)₂ O in the presence of pyridine or with an isopropenylester of the formula CH₂ ═C(CH₃)O--CO--R⁷ in the presence ofp-toluenesulfonic acid, or etherified in a known manner by reaction witha lower alkyl halide, basic etherification, or an R⁷ OH/sulfuric acidmixture, acidic etherification.

The compounds referred to hereinafter as intermediates or startingmaterials, insofar as they are not known, can be prepared according toknown methods. Thus, for example, the ketone starting materials offormula V used in process embodiment (1) (a) can be prepared in a knownmanner by decarboxylating β-keto-esters of formula XIV with the relativeconfiguration with respect to the 1-, 7- and 9a-positions indicated inthe formula which follows: ##STR26## wherein X and Y are as previouslydescribed and R^(a) is lower alkyl, see, for instance, Example 1(b).

The β-keto-esters of formula XIV can, in turn, be prepared from thecorresponding unsaturated β-keto-esters of the formula ##STR27## whereinX, Y and R^(a) are as previously described, in a known manner byhydrogenation [see, for instance, Example 1(c)].

The β-keto-esters of formula XIII can be prepared from corresponding5-phenyl-2-piperidones which are optionally substituted in the phenylring according to known methods, see, for instance, Example 1(d).

The benzimidazolines of formula III-8 used as starting materials inprocess embodiment (6) can be prepared by hydrogenating thecorresponding unsaturated compounds of formula XV, with the relativeconfiguration in the 7- and 9a-positions indicated in the formula whichfollows: ##STR28## wherein X, Y, R³, R⁵ and R⁶ are as previouslydescribed.

By N-alkylating compounds of formula XV in a manner analogous to thatdescribed in connection with process embodiment (6), there are obtainedN-alkylated starting materials of formula IX.

The compounds of formula XV can, in turn, be prepared from theaforementioned β-keto-esters of formula XIV according to the processdescribed in Example 7b or in analogy thereto.

The compounds of formulas VI and VII hereinbefore can be preparedaccording to the process described in Examples 13 and 14 or in analogythereto.

The intermediates or starting materials of formulas V, VI, VII, IX, X,XIII, XIV and XV are new and therefore also form part of the invention.

The phenyl-quinolizidines of formula I provided by the invention possessvaluable pharmacological properties. More specifically, thephenyl-quinolizidines of formula I demonstrate central-depressant,tranquilizing and antiemetic activity. Further, as hereinbefore setforth, various subgroups of compounds of formulas II and III haveneuroleptic activity, and the compounds of formula IV have analgesicactivity. Therefore, the compounds of formula I can be used ascentral-depressant, tranquilizing and antiemetic agents. The subgroupscharacterized by formulas II and III can also be used as neurolepticagents, and the subgroup characterized by formula IV can also be used asanalgesic agents. Accordingly, the neuroleptic compounds can be used asantipsychotics in the treatment of psychoses and neuroses, the analgesiccompounds can be utilized in the control of pain, and the compoundshaving antiemetic activity can be utilized in the control of nausea.

The neuroleptic properties of the compounds of formula I of theinvention were determined numerically using the tests describedhereinafter:

"Pole Climbing" test (rat)

In this test, there was used, for each dosage, a group of 10 rats whichhad been trained to escape an electric shock, unconditioned stimulus,produced via the lattice floor immediately after an acoustic signal,conditioned stimulus, by jumping up a vertical isolated pole in theexperimental cage. The inhibition of the conditioned reaction in 50% ofthe rats during an observation time of 6 hours is defined by theparameter ED 50 BCR (Block of Conditioned Reflex) and the inhibition ofthe unconditioned reaction is defined by the parameter ED 10 BUR (Blockof Unconditioned Reflex).

Spiroperidol-binding test (in vitro)

In this in vitro test calf striatum was used as the receptor [Creese etal., Life Sci. 17, 993 (1975)] and incubated with [³ H] spiroperidol inanalogy to the method described by Fields et al., Brain Research 136,578 (1977). The IC 50, which is the concentration of the test substanceat which a 50% detachment of the specific binding of [³ H] spiroperidolon the receptor takes place, was determined from four differentconcentrations in a triple procedure, using a computer program.

Representative experimental results are compiled in Table A hereinafter:

                  TABLE A                                                         ______________________________________                                                      Pole-Climbing                                                                             Spiroperidol-                                                       BCR      BUR      binding                                                     ED.sub.50 i.p.                                                                         ED.sub.10 i.p.                                                                         IC.sub.50                                   Compound        (mg/kg)  (mg/kg)  (nanomolar)                                 ______________________________________                                        rac-(9aβ H)-2α-tert.-                                              Butyl-7β-(2,4-dichloro-                                                  phenyl) octahydro-2H-                                                                         6.4      5.4      79                                          quinolizin-2-ol HCl                                                           (-)-(2S,7R,9aR)-2-tert.-                                                      Butyl-7-(2,4-dichloro-                                                        phenyl) octahydro-2H-                                                                         4.7      3.8      41                                          quinolizin-2-ol HCl                                                           rac-1-[(9aβH)-7β-(o-                                                Chlorophenyl)octa-                                                            hydro-2H-quinolizin-2α-                                                                 1.75     4.55     5                                           yl]-5,6-dimethyl-2-                                                           benzimidazolinone HCl                                                         rac-1-[(9aβH)-7β-(o-                                                Chlorophenyl)octa-                                                            hydro-2H-quinolizin-2α-                                                                 0.21     0.41     10                                          yl]-5-trifluoromethyl-                                                        2-benzimidazolinone HCl                                                       rac-1-[(9aβH)-7β-(o-                                                Fluorophenyl) octahyro-                                                       2H-quinolizin-2α-yl]-5-                                                                 0.064    0.175                                                chloro-2-benzimidaz-                                                          olinone HCl                                                                   ______________________________________                                    

The analgesic properties of the compounds of formula I provided by theinvention were determined numerically using the tests describedhereinafter:

Writhing test (mouse)

Eight male mice (20-22 g.) per dosage, were used for this test. Sixtyminutes after oral administration of the test substance, the mice wereinjected intraperitoneally with 10 ml/kg of the test solution. Followinga latent period of 5 minutes, the number of animals in which no morethan one characteristic writhing symptom (convulsive stretching movementof the body) occurred over five minutes was registered. The ED 50 is thedosage at which 50% of the mice show no more than one writhing.

Hot-plate test (mouse)

Eight mice (20-22 g) were used per dosage. Sixty minutes after oraladministration of the test substance, the mice were placed on a heatedmetal plate of 60°±0.5° C. Untreated mice begin to lick their pawswithin a maximum of 10 seconds. The ED 50 is defined as the dosage atwhich 50% of the mice begin to lick their paws only after a latentperiod of more than 10 seconds.

Representative experimental results are compiled in Table B hereinafter:

                  TABLE B                                                         ______________________________________                                                           Writhing 60'                                                                             Hot-plate 60'                                                      ED.sub.50 p.o.                                                                           ED.sub.50 p.o.                                  Compound           mg/kg      mg/kg                                           ______________________________________                                        (+)-2-Butyloctahydro-7-                                                       phenyl-2H-quinolizin-2-yl                                                                        0.19       2.6                                             acetate HCl                                                                   rac-(9aβH)-2α-n-Butyl-7β-                                     phenyl-octahydro-2H-                                                                             0.75       25                                              quinozilin-2-yl acetate HCl                                                   rac-(9aβH)-2α-tert.Butyl-7β-                                  phenyl-octahydro-2H-                                                                             8.7        86                                              quinolizin-2-yl trifluoro-                                                    acetate HCl                                                                   rac-(9aβH)-2α-Phenyl-7β-(m-                                   methoxyphenyl)-octahydro-                                                                        2.8        12                                              2H-quinolizin-2-yl                                                            propionate HCl                                                                rac-(9aβH)-2β-Phenyl-7β-(o-                                    chlorophenyl)-octahydro-2H-                                                                      116        284                                             quinolizin-2-yl acetate HCl                                                   ______________________________________                                    

The phenyl-quinolizidines of formula I provided by the present inventioncan be used as medicaments, for example, in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, for example, in the form of tablets, coated tablets, dragees,hard and soft gelatin capsules, solutions, emulsions, suspensions or thelike. The pharmaceutical preparations can, however, also be administeredrectally, for example, in the form of suppositories; locally orpercutaneously, for example, in the form of salves, creams, gels orsolutions; or parenterally, for example, in the form of injectablesolutions.

For the preparation of tablets, coated tablets, dragees and hard gelatincapsules, the phenyl-quinolizidines of formula I can be processed withpharmaceutical inert, inorganic or organic excipients. Exemplary ofexcipients which can be used for tablets, dragees and hard gelatincapsules are lactose, maize starch or derivatives thereof, talc, stearicacid or salts thereof, or the like. Suitable excipients for soft gelatincapsules are, for example, vegetable oils, waxes, fats, semi-solid,liquid polyols or the like. While no excipients are generally required,in the case of soft gelatin capsules, an excipient may be necessary dueto the nature of the active ingredient. Suitable excipients for thepreparation of solutions and syrups are, for example, water, polyols,saccharose, invert sugar, glucose and the like. Suitable excipients forinjectable solutions are, for example, water, alcohols, polyols,glycerine, vegetable oils, or the like. Suitable excipients forsuppositories, or for local or percutaneous administration forms are,for example, natural or hardened oils, waxes, fats, semi-liquid orliquid polyols or the like.

The pharmaceutical preparations can, moreover, also contain preservingagents, solubilizing agents, stabilizing agents, wetting agents,emulsifying agents, sweetening agents, coloring agents, flavoringagents, salts for varying the osmotic pressure, buffers, coating agentsor antioxidants. They can also contain other therapeutically valuablesubstances.

In the aforementioned pharmaceutical preparations, the dosages at whichthe compounds of formula I can be administered can lie in theapproximate range of 0.5-100 mg. In the case of oral administration, adosage of a compound of formula I of about 0.05 mg/kg to about 10 mg/kgper day comes into consideration and in the case of parenteraladministration, a dosage of a compound of formula I of about 0.01 mg/kgto 1 mg/kg per day comes into consideration.

The following Examples further illustrate the invention. Alltemperatures are stated in degrees Centigrade, unless otherwisementioned.

EXAMPLE 1

(a) 22.2 g. of rac-(9aβH)-7βl-(o-chlorophenyl)octahydro-2H-quinolizin-2-one dissolved in 300 ml. ofabsolute tetrahydrofuran are added dropwise under argon with strongstirring to a solution, cooled to -75° C., of tert.butyllithium inpentane (100 ml; 1.2 molar). Subsequently, the mixture is left at -75°C. for a further 30 minutes and then worked up as follows: The mixtureis hydrolyzed by adding 100 ml. of saturated ammonium chloride solutionand is then partitioned between ethyl acetate and water. After repeatedextraction with ethyl acetate, the entire organic phase is dried overmagnesium sulfate and evaporated. From the residue the end product[rac-(9aβH)-2α-tert.butyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ol]can be crystallized as the hydrochloride salt from 1400 ml. of ethylacetate by conducting in gaseous hydrogen chloride; yield 20.4 g (71%);melting point 276°-278° C. An alternative purification procedurecomprises chromatographing the residue on silica gel with ether/hexane(1:1).

When in place ofrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-one there areused equimolar amounts of corresponding substituted ketones, thefollowing tert.butylcarbinols can be obtained:

                  TABLE 1                                                         ______________________________________                                        rac-(9aβ H)-2α-Tert.butyl-7β -(R.sub.a)                       octahydro-2H-quinolizin-2-                                                    ol:                                                                                                   M.p. ° C.                                      ______________________________________                                        R.sub.a =                                                                            phenyl           HCl salt  230 (dec.)                                         p-chlorophenyl   "         286-288                                            2,4-dichlorophenyl                                                                             "         270-272                                            2,6-dichlorophenyl                                                                             "         262-263                                            p-trifluoromethylphenyl                                                                        "         285-286                                     ______________________________________                                    

When in place of tert.butyllithium equimolar amounts of analogous alkyl-or aryllithium reagents are reacted with the corresponding ketones, thefollowing carbinols can be obtained:

                                      TABLE 2                                     __________________________________________________________________________    rac-(9aβH)-(R.sub.b)-7β-(R.sub.a )octahydro-2H-quinolizin-2-ol:                                    M.p. ° C.                               __________________________________________________________________________    R.sub.b =                                                                         2α-sec.butyl                                                                     R.sub.a =                                                                         2,4-dichloro-                                                                          HCl salt                                                                           244-246                                                         phenyl                                                           2α-n-butyl                                                                           2,4-dichloro-                                                                          "    227-230                                                         phenyl                                                           2α-isopropyl                                                                         2,4-dichloro-                                                                          "    201-205                                                         phenyl                                                           2(α + β)-methyl                                                                 2,4-dichloro-                                                                          "    149-151                                                         phenyl                                                           2α-n-butyl                                                                           phenyl   base 100-102                                            2α-phenyl                                                                            o-chlorophenyl                                                                         HCl salt                                                                           266-267                                            2β-phenyl                                                                             "        "    175°                                                                   amorphous                                          2α-phenyl                                                                            m-methoxyphenyl                                                                        base 153-155                                            2β-phenyl                                                                             "        "    122-124                                            2α-phenyl                                                                            phenyl   "    156-158                                            2β-phenyl                                                                             "        "     99-102                                            2α-m-methoxy-                                                                        "        .sup.1 H-NMR                                                                       (CDCl.sub.3):                                      phenyl                     3.77 (s)                                           2β-m-methoxy-                                                                         "        .sup.1 H-NMR                                                                       (CDCl.sub.3):                                      phenyl                     3.82 (s)                                           2α-p-chloro-                                                                         "        HCl salt                                                                           249-250                                            phenyl                                                                        2α-m-trifluoro-                                                                      p-chlorophenyl                                                                         base 119-123                                            methylphenyl                                                                  2β-m-trifluoro-                                                                       "        "    122-124                                            methylphenyl                                                              __________________________________________________________________________

(b) The rac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-one usedas the starting material can be prepared as follows:

76.2 g. of methylrac-1αH,9aβH)-7β-(o-chlorophenyl)-octahydro-2-oxo-2H-quinolizine-1-carboxylateare dissolved in 1.2 liters of 6 N hydrochloric acid and boiled atreflux for 3 hours. The cooled solution is subsequently poured on to iceand made alkaline with concentrated sodium hydroxide. Extraction withthree 500 ml. portions of methylene chloride and evaporation of theorganic phase, dried over magnesium sulfate, gives 68 g. of crudeproduct. 50.4 g. ofrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-one can becrystallized from ether/hexane; melting point 80°-82°-82° C. (81%).

When in place of methylrac-(1αH,9aβH)-7β-(o-chlorophenyl)octahydro-2-oxo-2H-quinolizine-1-carboxylateequimolar amounts of corresponding substituted β-keto-esters aredecarboxylated, the following products are obtained:

                  TABLE 3                                                         ______________________________________                                        rac-(9aβ H)-7β-(R.sub.a) octahydro-2H-quinolizin-2-one:                                      M.p. ° C.                                     ______________________________________                                        R.sub.a =                                                                           phenyl                       71-72                                            p-chlorophenyl               80-82                                            p-trifluoromethylphenyl      103-104                                          o-methylphenyl    IR (film)  1726 cm.sup.-1                                   m-methoxyphenyl   IR (film)  1726 cm.sup.-1                                   2,4-dichlorophenyl           116-117                                          2,6-dichlorophenyl           116-118                                          o-fluorophenyl               74-76                                      ______________________________________                                    

(c) The octahydro-carboxylate used as the starting material in paragraph1(b) can, in turn, be prepared from the correspondinghexahydro-carboxylate as follows:

180 g of methylrac-7-(o-chlorophenyl)-3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylateare suspended in 3.6 liters of monoglyme (dimethoxyethane), cooled to-30° C. and 1.33 liters of DIBAH (diisobutylaluminum hydride, 20%solution in toluene) are added while stirring. Subsequently, the mixtureis stirred for 1 hour at -20° C. to -30° C. and then hydrolyzed at thistemperature with 1.72 liters of 2 N sodium hydroxide. For theworking-up, the mixture is partitioned between 25 liters of water and 20liters of chloroform, the organic phase is washed with two 5 literportions of water, dried over magnesium sulfate and evaporated, therebeing obtained 185.2 g of crude product. 109 g of product can becrystallized from ether/hexane. By chromatography of the mother liquoron 1 kg of silica gel with ethyl acetate there are obtained 37 g ofproduct. The total yield of methylrac-(1αH,9aβH)-7β-(o-chorophenyl)-octahydro-2-oxo-2H-quinolizine-1-carboxylate is 136 g (81%); melting point122°-124° C.

When in place of methylrac-7-(o-chlorophenyl)-3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylateequimolar amounts of correspondingly substituted educts are reduced withDIBAH, the following compounds are obtained:

                  TABLE 4                                                         ______________________________________                                        Methyl rac-(1αH,9aβH)7β-(R.sub.a) octahydro-2-oxo-2H-quino    lizine-                                                                       1-carboxylate:                                                                                         M.p. ° C.                                     ______________________________________                                        R.sub.a =                                                                           phenyl                       114-116                                          p-chlorophenyl               102-105                                          p-trifluoromethylphenyl      108-111                                          o-methylphenyl               94-98                                            m-methoxyphenyl   IR (film)  1752, 1723,                                                                   1660 cm.sup.-1                                   2,4-dichlorophenyl           116-118                                          2,6-dichlorophenyl           130-131                                          o-fluorophenyl               109-110                                    ______________________________________                                    

(d) The hexahydro-carboxylate used as the starting material in paragraph1(c) can, in turn, be prepared as follows:

150 g of 5-(o-chlorophenyl)-2-piperidone are dissolved in 2 liters ofmethylene chloride and added dropwise at room temperature while stirringwithin 60 minutes to 410 g of triethyloxonium tetrafluoroborate(Meerwein salt) in 1 liter of methylene chloride. Subsequently, themixture is boiled at reflux for 4 hours and left at room temperature fora further 15 hours. 372 g of potassium carbonate in 370 ml. of water arethen added dropwise to the solution which is cooled to 0° C., themixture being stirred intensively. The mixture is stirred at roomtemperature for a further 2 hours, the methylene chloride phase issubsequently decanted off and the residue is extracted with two 500 ml.portions of methylene chloride. The methylene chloride phase, dried overpotassium carbonate, is concentrated to an oily, partially crystallineresidue, then boiled up in 1 liter of hexane and filtered while hot.From the filtrate there are obtained, after evaporation of the hexane,151.4 g of the oily lactim ether, namely,3-(o-chlorophenyl)-6-ethoxy-2,3,4,5-tetrahydropyridine [IR (film): 1684cm⁻¹ ].

The lactim ether (151.4 g) is dissolved in 1.4 liters of methanol, 1.3 gof anhydrous p-toluenesulfonic acid are added thereto and 85 g of3-oxo-5-pentenoic acid methyl ester (Nazarov reagent) are added within60 minutes. After 20 hours at room temperature, the readily volatileconstituents are removed in vacuo and the residue is subsequently takenup in methylene chloride and washed with 500 ml. of saturated sodiumcarbonate solution. The methylene chloride phase, dried over magnesiumsulfate, is concentrated and the residue is crystallized from 800 ml ofethyl acetate/ether (4:1). There are obtained 123.7 g (54%) of methylrac-7-(o-chlorophenyl)-3,4,6,7,8,9-hexahydro-2-oxo-2H-quinolizine-1-carboxylatehaving a melting point of 145°-147° C.

When in place of 5-(o-chlorophenyl)-2-piperidone equivalent amounts ofcorresponding substituted piperidones are used, the following compoundsare obtained:

                  TABLE 5                                                         ______________________________________                                        Methyl rac-7-(R.sub.a)-3,4,6,7,8,9-hexahydro-2-oxo-2H-                        quinolizine-1-carboxylate:                                                                           M.p. ° C.                                       ______________________________________                                        R.sub.a =                                                                              phenyl              148-149                                                   p-chlorophenyl      185-187                                                   p-trifluoromethylphenyl                                                                           144-145                                                   o-methylphenyl      183-184                                                   m-methoxyphenyl     133-134                                                   2,4-dichlorophenyl  153-155                                                   2,6-dichlorophenyl  159-162                                                   o-fluorophenyl      165-167                                          ______________________________________                                    

EXAMPLE 2

A solution of 12.2 g ofrac-(9aβH)-2α-tert.butyl-7β-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-olin 80 ml of methanol is treated with a solution of 13.3 g of(+)-2,2'-(1,1'-binaphthyl)-phosphoric acid in 250 ml of methanol and 250ml of methylene chloride. The separated jelly is brought into solutionwith 1.2 liters of hot methanol and subsequently evaporated to a volumeof 500 ml, the (+)-phosphate crystallizing out at 0° C.; 8.7 g (72.5%);melting point 288°-290° C. From the (+)-phosphate there can be liberatedwith ammonia the (+)-base[(+)(2R,7S,9aS)-2-tert.butyl-7-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-ol](4.2 g) which, dissolved in 50 ml of ethanol and treated with 2.5 ml of5 N hydrochloric acid in ethanol at 0° C., yields 4.0 g of(+)-hydrochloride salt; melting point 275°-276° C.; [α]_(D) =+23.1°(c=1% in methanol).

The mother liquor from the crystallization of the (+)-phosphate is madebasic with concentrated ammonia and extracted with ethyl acetate/ether(1:1). The organic phase is washed neutral with water, dried overmagnesium sulfate and evaporated, 7.7 g of base being obtained. Thisbase is brought into solution with 50 ml of methanol and 7.33 g of(-)-2,2'-(1,1'-binaphthyl)-phosphoric acid in 200 ml of methanol and 200ml of methylene chloride are added. The mixture is then concentrated to250 ml, 250 ml of acetone are added and the mixture is cooled to 0° C.8.2 g of (-)-phosphate crystallize out; melting point 279°-281° C. Thebase[(-)(2S,7R,9aR)2-tert.butyl-7-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-ol](4.2 g) liberated therefrom with ammonia is dissolved in 50 ml ofethanol and treated with 2.5 ml of 5 N hydrochloric acid in ethanol. At0° C. there crystallize out 4.1 g of (-)-hydrochloride salt; meltingpoint 275°-276° C.; [α]_(D) =-23.1° (c=1% in methanol).

The following enantiomers can be isolated in an analogous manner bycleavage of the corresponding racemates:

(+)-2-Butyloctahydro-7-phenyl-2H-quinolin-2-ol; base melting point99°-101° C., and

(-)-2-butyloctahydro-7-phenyl-2H-quinolizin-2-ol; base melting point99°-101° C.

EXAMPLE 3

From 0.54 g. of magnesium shavings in 5 ml. of absolute ether and 5 g.of m-bromobenzotrifluoride in 10 ml. of ether there is first prepared aGrignard reagent by boiling under reflux for 2 hours. To the suspension,cooled to 0° C., there are subsequently added dropwise 2.64 g. ofrac-(9aβH)-7β-(p-chlorophenyl)octahydro-2H-quinolizin-2-one [preparedaccording to Example 1(b)] in 25 ml. of absolute ether, and the mixtureis stirred for a further hour at room temperature under argon. For thehydrolysis, the mixture is treated with saturated ammonium chloridesolution and the product is extracted with methylene chloride. Theorganic phase, washed with saturated sodium chloride solution, is driedover magnesium sulfate and evaporated, there being obtained a residueweighing 4.60 g. After chromatography on silica gel with ethylacetate/methanol, this residue gives two diastereomeric products,namely:

1.4 g. ofrac-(9aβH)-2α-(m-trifluoromethylphenyl)-7β-(p-chlorophenyl)octahydro-2H-quinolizin-2-olhaving a melting point of 119°-123° C. (34%), and

1.2 g. ofrac-(9aβH)-2β-(m-trifluoromethylphenyl)-7β-(p-chlorophenyl)octahydro-2H-quinolizin-2-olhaving a melting point of 122°-124° C. (29%).

When equimolar amounts of analogous alkyl- or aryl-lithium reagents areused, the compounds listed in Example 1a, Table 2 can be obtained.

EXAMPLE 4

20.0 g. ofrac.-(9aβH)-2α-tert.butyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ol[prepared according to Example 1(a)] are dissolved in 130 ml. ofisopropenyl acetate and 11.7 g. of anhydrous p-toluenesulfonic acid areadded. The mixture is then boiled at reflux under argon for 1 hour whilestirring. After cooling the solution, a further 20 ml. of ether areadded. The solution is left to stand for 2 hours and then the separatedp-toluenesulfonate of the product is filtered off and dried, 22.5 g.being obtained. The base[rac-(9aβH)-2α-tert.butyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ylacetate] can be liberated from the p-toluenesulfonate with sodiumbicarbonate solution. The yield is 15.8 g. and the hydrochloride saltmelts at 241°-242° C.

When equimolar amounts of the alkylcarbinols listed in Example 1(a) areused in the reaction, the acetates mentioned in Table 6 are obtained:

                  TABLE 6                                                         ______________________________________                                        rac-(9aβH)-2α-(R.sub.b)-7 β-(R.sub.a)octahyro-2H-quinolizi    n-2-yl acetate:                                                                                         M.p. ° C.                                    ______________________________________                                        R.sub.b =                                                                           tert.butyl                                                                             R.sub.a =                                                                             phenyl    HCl salt                                                                             247-248                                     "                p-chlorophenyl                                                                          "      244-246                                     "                2,4-dichloro-                                                                           "      246-247                                                      phenyl                                                       n-butyl          phenyl    "      248-250                               ______________________________________                                    

(+)-(2-Butyloctahydro-7-phenyl-2H-quinolizin-2-yl acetate) HCl, meltingpoint 242°-243° C.;

(-)-(2-butyloctahydro-7-phenyl-2H-quinolizin-2-yl acetate) HCl, meltingpoint 242°-243° C.

EXAMPLE 5

5.0 g. ofrac-(9aβH)-2α-tert.butyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-olare dissolved in 20 ml. of pyridine and treated dropwise at roomtemperature within 15 minutes with 20 ml. of trifluoroacetic acidanhydride. After 22 hours at room temperature, the solution isevaporated in vacuo and the residue is dissolved in 50 ml. of tolueneand concentrated. Subsequently, the oily residue is chromatographed on100 g. of silica gel with ethyl acetate. The eluate yields 5.4 g. of theproduct base[rac-(9aβH)-2α-tert.butyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-yltrifluoroacetate]. The hydrochloride salt melts at 172°-173° C.

When equimolar amounts of the alkyl- or arylcarbinols listed in Examples1(a) and 3 are used for the reaction, the trifluoroacetates listed inTable 7 can be obtained:

                  TABLE 7                                                         ______________________________________                                        rac-(9aβH)-R.sub.b)-7β-(R.sub.a) octahydro-αH-quinolizin-2    -yl                                                                           trifluoroacetate:                                                                                       M.p. ° C.                                    ______________________________________                                        R.sub.b =                                                                           2α-tert.butyl                                                                       R.sub.a =                                                                             phenyl                                                                              HCl salt                                                                              170-172                                     2α-phenyl     phenyl                                                                              "       164-166                               ______________________________________                                    

When in place of tirfluoroacetic acid anhydride equimolar amounts of thealkyl- or arylcarbinols listed in Examples 1(a) and 3 are reacted withanalogous carboxylic acid anhydrides, the following carbinol acylatescan be obtained:

                                      TABLE 8                                     __________________________________________________________________________    rac-(9aβH)-(R.sub.b)-7β-(R.sub.a) octahydro-2H-quinolizin-2-yl-(    R.sub.c):                                                                                                      M.p. ° C.                             __________________________________________________________________________    R.sub.b =                                                                         2α-phenyl                                                                       R.sub.a =                                                                         o-chloro-                                                                           C = acetate                                                                          HCl 220-222                                                      phenyl       salt                                                 2β-phenyl                                                                            o-chloro-                                                                           "      HCl 218-220                                                      phenyl       salt                                                 2α-phenyl                                                                           phenyl                                                                              propionate                                                                           HCl 242-243                                                                   salt                                                 2α-phenyl                                                                           m-methoxy-                                                                          "      HCl 212-214                                                      phenyl       salt                                                 2β-phenyl                                                                            m-methoxy-                                                                          "      HCl 233-235                                                      phenyl       salt                                                 2α-m-methoxy-                                                                       phenyl                                                                              "      HCl 233-234                                          phenyl                   salt                                                 2β-m-methoxy-                                                                        phenyl                                                                              "      oxalate                                                                           120-122                                          phenyl                                                                    __________________________________________________________________________

EXAMPLE 6

(a) 3.0 g. ofrac-(9aβN)-2β-phenyl-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2-ol[prepared according to Example 1(a)] are dissolved in 75 ml. ofmethanol, treated within 15 minutes with 15 ml. of concentrated sulfuricacid and then boiled at reflux for 2 hours. The cooled solution ispoured on to concentrated sodium hydroxide/ice and extracted with three200 ml. portions of ethyl acetate. The organic phase, dried overmagnesium sulfate, gives, after concentration, 3.2 g. of crude productwhich is chromatographed on 300 g. of silica gel with hexane/ether.There are obtained 1.7 g. ofrac-(9aβH)-2β-methoxy-2-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizine.The hydrochloride salt melts at 258°-260° C.

When in place ofrac-(9aβH)-2β-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-olcorresponding substituted arylcarbinols are reacted with C₁ -C₄-alcohols, there are obtained in the following O--(C₁ -C₄)-alkylcompounds:

                  TABLE 9                                                         ______________________________________                                        rac-(9aβH)-2β-(R.sub.b)-2-phenyl-7β-(R.sub.a)octahydro-2H-q    uinolizine:                                                                                            M.p. °C.                                      ______________________________________                                        R.sub.b =                                                                            methoxy   R.sub.a = phenyl                                                                          HCl salt                                                                              277-279                                         ethoxy    "           "       254-255                                  ______________________________________                                    

(b) 0.5 g. ofrac-(9aβH)-2α-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ol[prepared according to Example 1(a)] are dissolved in 5 ml. of HMPA(hexamethylphosphoric acid triamide) and treated at 0° C. with 0.1 g. ofsodium hydride (50-60% in mineral oil). The mixture is stirred for 0.5hour at 0° C. and then 0.2 ml. of methyl iodide is added thereto.Subsequently, the mixture is stirred at room temperature for 15 hours.For the working-up, the mixture is poured into 50 ml. of water andextracted with two 50 ml. portions of ethyl acetate. The ethyl acetatephase is washed with three 50 ml. portions of water, dried overmagnesium sulfate and evaporated. Chromatography on 50 g. of silica gelwith hexane/ether gives 0.2 g. ofrac-(9aβH)-2β-methoxy-2-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizine.The hydrochloride salt melts at 258°-260° C.

EXAMPLE 7

(a) A solution of 7.45 g. ofrac-1-[7β-(o-chlorophenyl)-3,6,7,8,9,9aβ-hexahydro-4H-quinolizin-2-yl]-5,6-dimethyl-2-benzimidazolinonein 30 ml. of concentrated sulfuric acid and 300 ml. of absolute ethanolis hydrogenated at room temperature with 0.40 g. of platinum oxide for 6hours. Subsequently, the catalyst is filtered off, the filtrate isevaporated and the residue is partitioned between chloroform and 2 Nsodium hydroxide. The chloroform phase, dired over potassium carbonate,gives, after evaporation, 7.5 g. of crude product. For the purification,the hydrochloride salt is crystallized from methanol/ether, there beingobtained 6.7 g. ofrac-1-[(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5,6-dimethyl-2-benzimidazolinonehydrochloride having a melting point of 310° C. An alternativepurification comprises chromatographing the base on silica gel withmethylene chloride/methanol. The melting point of the base is 268°-272°C.

When in place ofrac-1-[7β-(o-chlorophenyl)-3,6,7,8,9,9aβ-hexahydro-4H-quinolizin-2α-yl]-5,6-dimethyl-2-benzimidazolinoneequimolar amounts of corresponding substituted educts are hydrogenatedwith the catalysts listed in Table 10, the following products areobtained:

                  TABLE 10                                                        ______________________________________                                        rac-1-[(9aβH)-7β-(R.sub.a)octahydro-2H-quinolizin-2α-yl]-(    B)-2-                                                                         benzimidazolinone:                                                                              Cata-                                                                         lyst:     M.p. °C.                                   ______________________________________                                        R.sub.a =                                                                           o-chloro-                                                                              B =    5,6-    PtO.sub.2                                                                            HCl  300-305                                   phenyl          dichloro       salt                                           o-chloro-       5,6-H   PtO.sub.2                                                                            HCl  315-318                                   phenyl                         salt                                           o-chloro-       5,6-    PtO.sub.2                                                                            HCl  229-235                                   phenyl          dimethoxy      salt                                           o-chloro-       5-(CH.sub.2).sub.4 -6                                                                 PtO.sub.2                                                                            HCl  245-250                                   phenyl                         salt                                           p-chloro-       5,6-H   PtO.sub.2                                                                            base 244-248                                   phenyl                                                                        p-chloro-       5,6-    PtO.sub.2                                                                            "    289-295                                   phenyl          dimethyl                                                      o-methyl-       5,6-H   10%    HCl  285-290                                   phenyl                  Pd/C   salt                                           o-methyl-       5,6-    10%    HCl  291-293                                   phenyl          dimethyl                                                                              Pd/C   salt                                           o-methyl-       5,6-    PtO.sub.2                                                                            base 294-297                                   phenyl          dichloro                                                      phenyl          5,6-H   10%    HCl  223-228                                                           Pd/C   salt                                           phenyl          5,6-    10%    HCl  295-302                                                   dimethyl                                                                              Pd/C   salt                                           phenyl          5,6-    PtO.sub.2                                                                            base 295-300                                                   dichloro                                                      phenyl          5,6-    10%    "    248-250                                                   dimethoxy                                                                             Pd/C                                                  o-fluoro-       5,6-    10%    HCl  >300                                      phenyl          dimethyl                                                                              Pd/C   salt                                           o-fluoro-       5,6-    PtO.sub.2                                                                            HCl  >250                                      phenyl          dichloro       salt                                           o-fluoro-       5,6-    PtO.sub.2                                                                            HCl  >300                                      phenyl          difluoro       salt                                           o-fluoro-       5-(CH.sub.2).sub.4 -6                                                                 PtO.sub.2                                                                            HCl  248-250                                   phenyl                         salt                                     ______________________________________                                    

(b) Therac-1-[7β-(o-chlorophenyl)-3,6,7,8,9,9aβ-hexahydro-4H-quinolizin-2-yl]-5,6-dimethyl-2-benzimidazolinoneused as the starting material can be prepared as follows:

6.35 g. of 4,5-dimethyl-1,2-phenylenediamine are dissolved in 100 ml. ofxylene, heated to reflux and there are added within 2 hours 15 g. ofmethylrac-(1αH,9aβH)-7β-(o-chlorophenyl)octahydro-2-oxo-2H-quinoline-1-carboxylate[prepared according to Example 1(c)] in 100 ml. of xylene. The mixtureis then boiled under reflux for 7 hours and subsequently cooled down.From the solution there crystallize out 13.65 g. ofrac-1-[7β-(o-chlorophenyl)-3,6,7,8,9,9aβ-hexahydro-4H-quinolizin-2-yl]-5,6-dimethyl-2-benzimidazolinonehaving a melting point of 239°-241° C.

When in place of methylrac-(1αH,9aβH)-7β-(o-chlorophenyl)octahydro-2-oxo-2H-quinolizine-1-carboxylateequimolar amounts of corresponding substituted β-ketoesters are reactedwith 1,2-phenylene-diamines the following compounds are obtained:

                  TABLE 11                                                        ______________________________________                                        rac-1-[7β-(R.sub.a)-3,6,7,8,9,9aβ-hexahydro-4H-quinolizine-2-yl]    (B)-2-benzimidazolinone:                                                                               M.p. °C.                                      ______________________________________                                        R.sub.a =                                                                           o-chloro- B =    5,6-dichloro                                                                           HCl salt                                                                             281-284                                      o-chloro-        5,6-H    "      267-269                                      o-chloro-        5,6-dimethoxy                                                                          "      225 (dec.)                                   o-chloro-        5-(CH.sub.2).sub.4 -6                                                                  base   246-249                                      p-chloro-        5,6-H    HCl salt                                                                             274-277                                      phenyl                                                                        p-chloro-        5,6-dimethyl                                                                           "      228-230                                      phenyl                                                                        o-methyl-        5,6-H    "      277-279                                      phenyl                                                                        o-methyl-        5,6-dimethyl                                                                           "      226-230                                      phenyl                                                                        o-methyl-        5,6-dichloro                                                                           "      286-289                                      phenyl                                                                        phenyl           5,6-dimethyl                                                                           base   259-262                                      phenyl           5,6-dichloro                                                                           "      293-296                                      phenyl           5,6-dimethoxy                                                                          "      241-243                                      2'-methoxy-      5,6-dimethyl                                                                           "      248-251                                      5'-chloro-                                                                    phenyl                                                                        o-fluoro-        5,6-dimethyl                                                                           "      260-263                                      phenyl                                                                        o-fluoro-        5,6-dichloro                                                                           "      298-302                                      phenyl                                                                        o-fluoro-        5,6-difluoro                                                                           "      257-259                                      phenyl                                                                        o-fluoro-        5-(CH.sub.2).sub.4 -6                                                                  "      238-241                                      phenyl                                                                  ______________________________________                                    

EXAMPLE 8

3.0 g. ofrac-1-[(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl)]-2-benzimidazolinone[prepared according to Example 7(a)] are suspended in 30 ml. of drymonoglyme, treated with 0.41 g. of sodium hydride (50-60% in mineraloil) and stirred at room temperature for 1 hour. Subsequently, themixture is cooled to 0° C. and 1.23 g. of methyl iodide are added. After30 minutes at room temperature, the mixture is poured into 50 ml. ofwater and extracted with ethyl acetate. The organic phase, dried overmagnesium sulfate, is concentrated and the crude product ischromatographed on silica gel with methylene chloride/methanol. Thereare obtained 2.10 g. ofrac-1-[9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-yl]-3-methyl-2-benzimidazolinone.The hydrochloride salt melts at 315°-320° C.

EXAMPLE 9

0.5 g. ofrac-1-[(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5,6-dimethyl-2-benzimidazolinone[prepared according to Example 7(a)] is heated to 150° C. for 3 hourswith 1.0 g. of phosphorus pentasulfide in 5 ml. of pyridine. The mixtureis then evaporated and the residue is partitioned between 2 N sodiumhydroxide and chloroform/isopropanol. The organic phase is washed withsaturated sodium chloride solution, dried over magnesium sulfate andevaporated. Chromatography of the crude product on silica gel withmethylene chloride/methanol gives 0.22 g. ofrac-1-[(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5,6-dimethyl-2-benzimidazolinethionehaving a melting point of 293°-297° C.

EXAMPLE 10

(a) A solution of 7.20 g. ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toluidino)-2H-quinolizinein 180 ml. of methylene chloride is treated with 4.59 g. of 93%N,N'-carbonyldiimidazole and the mixture is stirred at room temperatureovernight. The separated product is filtered off after 20 hours, washedwith three 100 ml. portions of methylene chloride and subsequentlydried. There are obtained 6.45 g. of crystallinerac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5-(trifluoromethyl)-2-benzimidazolinonehaving a melting point of 304°-306° C.

When in place ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toluidino)-2H-quinolizinecorresponding substituted phenylene-diamines are reacted withN,N'-carbonyldiimidazole, the following compounds are obtained:

                  TABLE 12                                                        ______________________________________                                        rac-1-[(9aβ H)-7β-(R.sub.a)octahydro-2H-quinolizin-2                α-yl]-(B)-2-benzimidazolinone:                                                            M.p. °C.                                             ______________________________________                                        R.sub.a =                                                                           o-fluoro-                                                                              B =    5-chloro                                                                              283-285                                                                              (base); 298-304                                phenyl                         (HCl salt)                                     o-chloro-       5-chloro                                                                              223-230                                                                              (base)                                         phenyl                                                                        o-chloro-       5-trifluoro-                                                                          257-259                                                                              (base); 240-245                                phenyl          methyl         (HCl salt)                                     o-chloro-       5,6-dichloro                                                                          300-305                                                                              (HCl salt)                                     phenyl                                                                        o-fluoro-       5,6-dichloro                                                                          >250   (HCl salt)                                     phenyl                                                                  ______________________________________                                    

(b) Therac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toluidino)-2H-quinolizineused as the starting material in paragraph (a) of this Example can beprepared as follows:

25.7 g. ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-nitro-p-toluidino)-2H-quinolizineare hydrogenated in 0.9 liter of tetrahydrofuran and 0.9 liter ofmethanol with 13 g. of Raney nickel for 20 hours at room temperature andatmospheric pressure. The catalyst is then removed by suction filtrationand the filtrate is evaporated. There are obtained 23.6 g. ofcrystallinerac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toluidino)-2H-quinolizinewhich, if desired, can be recrystallized from alcohol/ethyl acetate;melting point 133°-138°.

If in place ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-nitro-p-toluidino)-2H-quinolizinecorresponding substituted nitro compounds are reduced, the followingcompounds are obtained:

                  TABLE 13                                                        ______________________________________                                        rac-(9aβH)-7β-(R.sub.a)octahydro-2α-(B)-2H-quinolizine:                                 M.p. °C.                                     ______________________________________                                        R.sub.a =                                                                           o-fluorophenyl                                                                            B =    2-amino-4-chloro-                                                                          137-141                                                          anilino                                                    o-fluorophenyl     2-amino-4,5-dichloro-                                                                      164-166                                                          anilino                                                    o-chlorophenyl     2-amino-4-chloro-                                                                          170-172                                                          anilino                                                    o-chlorophenyl     2-amino-4,5-dichloro-                                                                      148-150                                                          anilino                                                    o-chlorophenyl     α',α',α'-trifluoro-2-                                                    151-153                                                          amino-p-toluidino                                    ______________________________________                                    

(c) Therac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-nitro-p-toluidino)-2H-quinolizineused as the starting material in paragraph (b) of this Example can beprepared as follows:

20.0 g. ofrac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)-octahydro-2H-quinolizine aredissolved in 300 ml. of cyclohexanol having a purity above 99%, treatedwith 8.62 g. of anhydrous sodium carbonate and heated to 160° C. At thistemperature there is added dropwise within 3 hours a solution of 20.0 g.of 4-chloro-3-nitro-benzotrifluoride in 200 ml. of cyclohexanol having apurity above 99%. The solution is then held at 160° C. for a further 4hours. After cooling to room temperature, inorganic solids are filteredoff and the filtrate is evaporated in vacuo. The residue is dissolved in500 ml. of hot ethyl acetate, 5 g. of active carbon are added to thesolution and the mixture is boiled at reflux for 5 minutes. The mixtureis then filtered while hot through Hyflo Super Cel, the filtrate isconcentrated to 200 ml. and 100 ml. of n-hexane are added. Therecrystallize 22.3 g. ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-nitro-p-toluidino)-2H-quinolizinehaving a melting point of 163°-165° C. By chromatography of the motherliquor on 250 g. of silica gel with n-hexane/ethyl acetate (4:1) thereare obtained a further 5.45 g. of product. The total yield is 78.8%.

Where in place ofrac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)octahydro-2H-quinolizinecorresponding substituted amino-quinolizidines are reacted withcorresponding substituted o-chloro-nitrobenzenes, the followingcompounds are obtained:

                  TABLE 14                                                        ______________________________________                                        rac-(9aβH)-7β-(R.sub.a)octahydro-2α-(B)-2H-quinolizine:                                 M.p. °C.                                     ______________________________________                                        R.sub.a =                                                                           o-fluorophenyl                                                                            B =    2-nitro-4-chloro-                                                                          185-187                                                          anilino                                                    o-fluorophenyl     2-nitro-4,5-dichloro-                                                                      202-203                                                          anilino                                                    o-chlorophenyl     2-nitro-4-chloro-                                                                          183-185                                                          anilino                                                    o-chlorophenyl     2-nitro-4,5-dichloro-                                                                      197-199                                                          anilino                                                    o-chlorophenyl     α',α',α'-trifluoro-2-                                                    154-155                                                          nitro-p-toluidino                                    ______________________________________                                    

(d) Therac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)octahydro-2H-quinolizine usedas the starting material in paragraph (c) can be prepared as follows:

84.3 g. of rac-(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2-one[see Example 1(b), Table 3] are heated at reflux for 1.5 hours in 1700ml. of methanol with 47.4 g. of hydroxylamine hydrochloride and 94.3 g.of anhydrous potassium carbonate. The methanol is subsequently distilledoff and the residue is partitioned between 750 ml. of water, 600 ml. ofchloroform and 150 ml. of isopropanol. The aqueous phase isback-extracted twice with in each case 250 ml. of a mixture of 200 ml.of chloroform and 50 ml. of isopropanol, the combined organic phases aredried over magnesium sulfate and then evaporated. There are obtained85.3 g. of oxime which is dissolved in 1.5 liters of tetrahydrofuran,0.5 liter of alcohol and 1 liter of 5% (g/g) ammonia in alcohol andhydrogenated with 45 g. of Raney nickel for 30 hours at room temperatureand atmospheric pressure. The catalyst is then filtered off and thefiltrate is evaporated. From the residue there can be crystallized bydissolution in 400 ml. of alcohol and addition of 130 ml. of 5 Nhydrogen chloride in alcohol 53.5 g. of the dihydrochloride salt ofrac-(9aβH)-7β-(o-fluorophenyl)-2α-(amino)octahydro-2H-quinolizine havinga melting point of 299°-302° C. The diastereomericrac-(9aβH)-7β-(o-fluorophenyl)-2β-(amino)octahydro-2H-quinolizine isdissolved as the dihydrochloride in the mother liquor.

When in place ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2-one thecorresponding substituted quinolizidinone is aminated, there is obtainedthe following compound:

                  TABLE 15                                                        ______________________________________                                        rac-(9aβ H)-7 β-(R.sub.a)-2α-(amino)octahydro-2H-quinolizi    ne:                                                                                           M.p. °C.                                               ______________________________________                                        R.sub.a = o-chlorophenyl                                                                        293-296 (2 HCl)                                             ______________________________________                                    

EXAMPLE 11

A solution of 7.20 g. ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toluidino)-2H-quinolizine[prepared according to Example 10(b)] in 180 ml. of methylene chlorideis treated with 4.75 g. of N,N'-thiocarbonyldiimidazole and the mixtureis stirred at room temperature overnight. After 20 hours, the separatedproduct is filtered off, washed with two 100 ml. portions of methylenechloride and subsequently dried. There are obtained 5.80 g. ofcrystallinerac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5-(trifluoromethyl)-2-benzimidazolinthionehaving a melting point of 308°-309° C.

When in place ofrac-(9aβH)-7β-(o-fluorophenyl)octahydro-2α-(α',.alpha.',α'-trifluoro-2-amino-p-toludino)-2H-quinolizinecorresponding substituted phenylene-diamines are reacted withN,N-thiocarbonyldiimidazole, the following compounds are obtained:

                  TABLE 16                                                        ______________________________________                                        rac-1-[(9aβH)-7β-(R.sub.a)octahydro-2H-quinolizin-2α-yl]-(    B)-2-                                                                         benzimidazolinthione:                                                                                  M.p. °C.                                      ______________________________________                                        R.sub.a =                                                                            o-fluorophenyl                                                                             B =     5-chloro >300                                            o-fluorophenyl       5,6-dichloro                                                                           >310                                            o-chlorophenyl       5-chloro 264-267                                         o-chlorophenyl       5,6-dichloro                                                                           >295                                     ______________________________________                                    

EXAMPLE 12

A solution of 5.80 g. ofrac-(9aβH)-2α-(2-amino-4,5-dichloro-anilino)-7β-(o-chlorophenyl)octahydro-2H-quinolizine[see Example 10(b)] in 60 ml. of m-xylene is boiled at reflux for 6hours with 20 ml. of triethyl orthoacetate. The solution is cooled down,poured into cold 2 N sodium hydroxide and extracted twice with 300 ml.of methylene chloride each time. The organic phase, dried over anhydroussodium carbonate, is subsequently evaporated. The residue is dissolvedin 50 ml. of 5 N hydrochloric acid in alcohol and heated to reflux for 1hour. The separated dihydrochloride of the product is filtered off anddried. There are obtained 5.60 g. of the dihydrochloride salt ofrac-(9aβH)-7β-(o-chlorophenyl)-2α-(5,6-dichloro-2-methyl-1-benzimidazolyl)octahydro-2H-quinolizinehaving a melting point of 231°-236° C. The yield is 77%.

Where in place ofrac-(9aβH)-2α-(2-amino-4,5-dichloroanilino)-7β-(o-chlorophenyl)octahydro-2H-quinolizinethe corresponding substituted phenylene-diamine is reacted with triethylorthoacetate, the following compound can be obtained:

                  TABLE 17                                                        ______________________________________                                        rac-(9aβH)-7β-(R.sub.a)-2α-[(B)-2-methyl-1-benzimidazolyl]    octa-                                                                         hydro-2H-quinolizine 2 HCl:                                                                          M.p. °C.                                        ______________________________________                                        R.sub.a = o-chlorophenyl                                                                     B = 5-chloro  240-245                                          ______________________________________                                    

EXAMPLE 13

2.70 g. of a 1:1 mixture ofrac-(9aβH)-2-phenyl-7β-(o-chlorophenyl)-3,4,6,7,8,9-hexahydro-2H-quinolizineandrac-(9aβH)-2-phenyl-7β-(o-chlorophenyl)-1,4,6,7,8,9-hexahydro-2H-quinolizineare boiled under reflux for 15 hours with 70 ml. of water and 14 ml. of98% sulfuric acid. The solution is cooled down, poured into a saturatedaqueous potassium carbonate solution, diluted with 200 ml. of water andextracted with three 200 ml. portions of ethyl acetate. The combinedethyl acetate extracts are dried over magnesium sulfate and evaporated.The crude product (2.35 g.) is chromatographed over 100 g. of silica gelusing ethyl acetate for the elution. 1.55 g. of educt mixture arerecovered in a first fraction and from a further fraction there can beobtained 0.15 g. (yield 3.5%) ofrac-(9aβH)-2α-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ol.The hydrochloride salt melts at 265°-275° C.

The double-bond isomer mixture used as the starting material can beobtained as follows:

5.00 g. ofrac-(9aβH)-2β-phenyl-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2-ol[see Example 1(a), Table 2] are dissolved in 25 ml. of pyridine and 2.1ml. of thionyl chloride are added. After standing at room temperaturefor 2 hours, the mixture is evaporated in vacuo and subsequentlypartitioned between chloroform and water. The organic phase, dried overmagnesium sulfate, is evaporated and the crude product (3.90 g.) isfiltered with ethyl acetate over 200 g. of aluminum oxide (activityIII). In this manner there can be eluted 2.75 g. of a 1:1 mixture ofrac-(9aβH)-2-phenyl-7β-(o-chlorophenyl)-3,4,6,7,8,9-hexahydro-2H-quinolizineandrac-(9aβH)-2-phenyl-7β-(o-chlorophenyl)-1,4,6,7,8,9-hexahydro-2H-quinolizine;NMR (CDCl₃): 5.93+6.08 ppm (in each case 2 broad singlets in the ratio1:1, together 1 proton).

EXAMPLE 14

0.068 g. of sodium hydride (50% in mineral oil), suspended in 10 ml. of1,2-dimethoxyethane, is treated with 0.160 g. of benzimidazolinone andsubsequently with 0.500 g. of a 1:1 mixture ofrac-(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2α-ylp-toluenesulfonate andrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2β-ylp-toluenesulfonate in 10 ml. of 1,2-dimethoxyethane and the mixture isthen heated to reflux for 45 hours. After cooling, the mixture ispartitioned between chloroform and water, the organic phase is driedover magnesium sulfate and evaporated. The resulting crude product(0.450 g.) is chromatographed on 50 g. of silica gel using chloroformcontaining 1% methanol for the elution, there being obtained 0.040 g.(9% yield) ofrac-1-[(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-2-benzimidazolinone.The hydrochloride salt melts at 315°-317° C.

The 1:1 mixture of diastereomeric p-toluenesulfonates used as thestarting material can be prepared as follows:

5.00 g. of rac-(9aβH)-7β-(o-chlorophenyl)-octahydro-2H-quinolizin-2-one[see Example 1(b)] in 50 ml. of methanol are treated with 0.7 g. ofsodium borohydride and stirred at room temperature for 45 minutes.Subsequently, the mixture is partitioned between water and ethylacetate, the organic phase is dried over magnesium sulfate andconcentrated. The crude product obtained is chromatographed over 200 g.of silica gel with diethyl ether and the eluate is evaporated, therebeing obtained 5.0 g. of a mixture of diastereomeric alcohols. Themixture of the alcohols is dissolved in 50 ml. of pyridine and 7.3 g. ofp-toluenesulfonic acid chloride are added thereto. After stirring atroom temperature for 2 hours, the mixture is evaporated, the residue ispartitioned between 2 N sodium hydroxide and ethyl acetate and, afterdrying, the organic phase is concentrated. By chromatography on 100 g.of silica gel with methylene chloride containing 1% methanol there canbe obtained 2.20 g. of a 1:1 mixture ofrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2β-ylp-toluenesulfonate andrac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-ylp-toluenesulfonate [NMR (CDCl₃): 2 singlets 2.33+2.43 ppm] as well as5.80 g. of rac-(9aβH)-7β-(o-chlorophenyl)octahydro-2H-quinolizin-2α-ylp-toluenesulfonate [NMR (CDCl₃): 1 singlet 2.43 ppm].

The following Examples illustrate pharmaceutical preparations containingthe phenyl-quinolizidines provided by the present invention:

EXAMPLE A

    ______________________________________                                        Tablets                Per Tablet                                             ______________________________________                                        (-)-(2S,7R,9aR)-2-Tert.butyl-7-(2,4-                                           dichlorophenyl)octahydro-2H-quino-                                            lizin-2-ol HCl        100 mg.                                                Lactose                202 mg.                                                Maize starch            80 mg.                                                Hydrolyzed maize starch                                                                               20 mg.                                                Calcium stearate        8 mg.                                                 Total Weight           410 mg.                                                ______________________________________                                    

The(-)-(2S,7R,9aR)-2-tert.butyl-7-(2,4-dichlorophenyl)octahydro-2H-quinolizin-2-olhydrochloride, the lactose, the maize starch and the hydrolyzed maizestarch are mixed and granulated with water to a viscous paste. Thispaste is passed through a sieve and subsequently dried overnight at 45°C. The dried granulate is passed through a sieve and subsequently mixedwith the calcium stearate. The resulting mixture is pressed to tabletsweighing 410 mg. and having a diameter of about 10 mm.

EXAMPLE B

    ______________________________________                                        Tablets                Per Tablet                                             ______________________________________                                        (+)-2-Butyloctahydro-7-phenyl-2H-quinoli-                                      zin-2-yl acetate HCl   10.0 mg.                                              Lactose                129.0 mg.                                              Maize starch            50.0 mg.                                              Gelatinized maize starch                                                                              8.0 mg.                                               Calcium stearate        3.0 mg.                                               Total Weight           200.0 mg.                                              ______________________________________                                    

The (+)-2-butyloctahydro-7-phenyl-2H-quinolizin-2-yl acetatehydrochloride, the lactose, the maize starch and the gelatinized maizestarch are intimately mixed with one another. The mixture is passedthrough a comminuting machine and subsequently moistened with water to athick paste. The moist mass is passed through a sieve. The moistgranulate is dried at 45° C. The dried granulate is mixed thoroughlywith the calcium stearate. The granulate is now pressed to tabletsweighing 200 mg. and having a diameter of about 8 mm.

EXAMPLE C

    ______________________________________                                        Tablets                Per Tablet                                             ______________________________________                                        rac-1-[(9aβ H)-7 β-(o-fluorophenyl)octa-                             hydro-2H-quinolizin-2α-yl]-5-chloro-                                    2-benzimidazoline HCl  10.0 mg.                                              Lactose                129.0 mg.                                              Maize starch            50.0 mg.                                              Gelatinized maize starch                                                                              8.0 mg.                                               Calcium stearate        3.0 mg.                                               Total Weight           200.0 mg.                                              ______________________________________                                    

Therac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5-chloro-2-benzimidazolinehydrochloride, the lactose, the maize starch and the gelatinized maizestarch are intimately mixed with one another. The mixture is passedthrough a comminuting machine and subsequently moistened with water to athick paste. The moist mass is passed through a sieve. The moistgranulate is dried at 45° C. The dried granulate is mixed thoroughlywith the calcium stearate. The granulate is now pressed to tabletsweighing 200 mg. and having a diameter of about 8 mm.

EXAMPLE D

    ______________________________________                                        Tablets                Per Tablet                                             ______________________________________                                        (-)-(2S,7R,9aR)-2-Tert.butyl-7-(2,4-                                           dichlorophenyl)octahydro-2H-quinoli-                                          zin-2-ol HCl           20.0 mg.                                              Lactose                115.0 mg.                                              Maize starch            61.0 mg.                                              Talc                    3.4 mg.                                               Magnesium stearate      0.6 mg.                                               Total Weight           200.0 mg.                                              ______________________________________                                    

The ingredients are intimately mixed with one another and pressed totablets each weighing 200 mg. Subsequently, the tablets are coated withethyl cellulose and Carbowax.

EXAMPLE E

    ______________________________________                                        Capsules               Per Capsule                                            ______________________________________                                        rac-1-[(9aβ H)-7β-(o-fluorophenyl)octa-                              hydro-2H-quinolizin-2α-yl]-5-chloro-                                    2-benzimidazolone HCl  10.0 mg.                                              Lactose                175.0 mg.                                              Maize starch            30.0 mg.                                              Talc                    5.0 mg.                                               Total Weight           220.0 mg.                                              ______________________________________                                    

Therac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5-chloro-2-benzimidazolonehydrochloride, the lactose and the maize starch are intimately mixedwith one another and passed through a comminuting machine. The mixtureis now mixed thoroughly with the talc and filled into hard gelatincapsules.

EXAMPLE F

    ______________________________________                                        Capsules               Per Capsule                                            ______________________________________                                        (+)-2-Butyloctahydro-7-phenyl-2H-                                              quinolizin-2-yl acetate HC1                                                                          10.0 mg.                                              Lactose                175.0 mg.                                              Maize starch            30.0 mg.                                              Talc                    5.0 mg.                                               Total Weight           220.0 mg.                                              ______________________________________                                    

The (+)-2-butyloctahydro-7-phenyl-2H-quinolin-2yl acetate hydrochloride,the lactose and the maize starch are intimately mixed with one anotherand passed through a comminuting machine. The mixture is now mixedthoroughly with the talc and filled into hard gelatin capsules.

EXAMPLE G

    ______________________________________                                        Parenteral administration form (0.2 mg)                                       Each 1 ml. ampul contains:                                                    ______________________________________                                        rac-1-[(9aβH)-7 β-(o-fluorophenyl)octahydro-                         2H-quinolizin-2α -yl]-5-chloro-2-benz-                                                           0.204 mg.                                            imidazolone HCl         (2% excess)                                          Glucose for injection    40.0 mg.                                             Water for injection q.s. ad                                                                             1.0 ml.                                             ______________________________________                                    

2.04 g. ofrac-1-[(9aβH)-7β-(o-fluorophenyl)octahydro-2H-quinolizin-2.alpha.-yl]-5-chloro-2-benzimidazolonehydrochloride are treated with 400 g. of glucose, dissolved in water forinjection, and made up to a volume of 10,000 ml. with water forinjection. The solution is either filtered sterile and filled intocolorless ampuls which are gassed with nitrogen and sealed or filledinto colorless ampuls which are gassed with nitrogen, sealed andsubsequently sterilized with a current of steam for 30 minutes orautoclaved at 120° C.

EXAMPLE H

    ______________________________________                                        Parenteral administration form (0.5 mg)                                       Each 1 ml. ampul contains:                                                    ______________________________________                                        (+)-2-Butyloctahydro-7-phenyl-2H-quinoli-                                                              0.510 mg.                                             zin-2-yl acetate HCl    (2% excess)                                          Glucose for injection    40.0 mg.                                             Water for injection q.s. ad                                                                            1.0 ml.                                              ______________________________________                                    

5.10 g. of (+)-2-butyloctahydro-7-phenyl-2H-quinoline-2-yl acetatehydrochloride are treated with 400 g. of glucose, dissolved in water forinjection, and made up to a volume of 10,000 ml. with water forinjection. The solution is either filtered sterile and filled intocolorless ampuls which are gassed with nitrogen and sealed or filledinto colorless ampuls which are gassed with nitrogen, sealed andsubsequently sterilized with a current of steam for 30 minutes orautoclaved at 120° C.

We claim:
 1. A compound of the formula ##STR29## wherein X, Y, R¹ and R²are as follows: X is hydrogen, fluorine, chlorine, lower alkoxy, loweralkyl or trifluoromethyl; Y is hydrogen, fluorine, chlorine, loweralkoxy or lower alkyl; R¹ is hydroxy, lower alkoxy, lower alkanoyloxy,optionally substituted by halogen, or, when R² is the group Ahereinafter described, hydrogen; R² is lower alkyl, phenyl, phenylsubstituted by halogen, lower alkoxy or trifluoromethyl, or when R¹ ishydrogen, a group A of the formula ##STR30## wherein R³, R⁴, R⁵ and R⁶are as follows: R³ is oxygen or sulfur; R⁴ is hydrogen or lower alkyl;R⁵ and R⁶, independently, are hydrogen, methyl, fluorine, chlorine,methoxy or trifluoromethyl, or taken together are --(CH₂)₄ --,itsracemate, an enantiomer thereof, or a pharmaceutically acceptable acidaddition salt thereof.
 2. A compound in accordance with claim 1, whereinR² is lower alkyl, phenyl, phenyl substituted by halogen, lower alkoxyor trifluoromethyl, or when R¹ is hydrogen, a group A of the formula##STR31## wherein R³ is oxygen or sulfur, R⁴ is hydrogen or lower alkyl;and R⁵ and R⁶, independently, are hydrogen, methyl, chlorine or methoxy.3. A compound in accordance with claim 1 of the formula ##STR32##wherein X is hydrogen, fluorine, chlorine, lower alkoxy, lower alkyl ortrifluoromethyl; Y is hydrogen, fluorine, chlorine, lower alkoxy orlower alkyl; and R² is lower alkyl, phenyl, phenyl substituted byhalogen, lower alkoxy or trifluoromethyl,its racemate, an enantiomerthereof, or a pharmaceutically acceptable acid addition salt thereof. 4.A compound in accordance with claim 3, wherein R² is branched-chainlower alkyl; X is fluorine or chlorine; Y is hydrogen, fluorine orchlorine; and X and Y are in the ortho- and/or para-position.
 5. Acompound in accordance with claim 4, wherein R² is tert.butyl, X iso-chloro and Y is p-chloro.
 6. A compound in accordance with claim 3,wherein R² is tert.butyl, X is p-trifluoromethyl and Y is hydrogen.
 7. Acompound in accordance with claim 1 of the formula ##STR33## wherein Xis hydrogen, fluorine, chlorine, lower alkoxy, lower alkyl ortrifluoromethyl; Y is hydrogen, fluorine, chlorine, lower alkoxy orlower alkyl; R³ is oxygen or sulfur; R⁴ is hydrogen or lower alkyl; R⁵and R⁶, independently, are hydrogen, methyl, fluorine, chlorine, methoxyor trifluoromethyl, or taken together are --(CH₂)₄ --,its racemate, anenantiomer thereof, or a pharmaceutically acceptable acid addition saltthereof.
 8. A compound in accordance with claim 7, wherein X ishydrogen, o-fluoro or o-chloro; Y is hydrogen; R³ is oxygen or sulfur;R⁴ is hydrogen; R⁵ is fluorine, chlorine or trifluoromethyl; and R⁶ ishydrogen, chlorine or fluorine.
 9. A compound in accordance with claim8, wherein X is o-chloro; Y is hydrogen; R³ is oxygen; R⁴ and R⁶ arehydrogen; and R⁵ is trifluoromethyl.
 10. A compound in accordance withclaim 8, wherein X is o-fluoro; Y is hydrogen; R³ is oxygen; R⁴ and R⁶are hydrogen; and R⁵ is chlorine.
 11. A compound in accordance withclaim 7, wherein X, Y, R³, R⁴, R⁵ and R⁶, each occurrence, are asfollows:(a) X=o-Cl; Y, R⁴, R⁵, R⁶ =H; and R³ =O, or (b) X=o-Cl; Y, R⁴=H; R³ =O; and R⁵, R⁶ =CH₃, or (c) X=o-Cl; Y, R⁴ =H; R³ =O; and R⁵, R⁶=Cl, or (d) X=o-Cl; Y, R⁵, R⁶ =H; R³ =O; and R⁴ =CH₃, or (e) X=o-Cl; Y,R⁴, R⁶ =H; R⁵ =CF₃ ; R³ =O, or (f) X=o-Cl; Y, R⁴, R⁶ =H; R⁵ =Cl; and R³=O, or (g) X=o-Cl; Y, R⁴, R⁶ =H; R⁵ =Cl; and R³ =S, or (h) X=o-Cl; Y, R⁴=H; R³ =S; and R⁵, R⁶ =Cl, or (i) X=o-Cl; Y, R⁴ =H; R³ =O; and R⁵ and R⁶together --(CH₂)₄ --, or (j) X=o-F; Y, R⁴ =H; R³ =O; and R⁵, R⁶ =CH₃, or(k) X=o-F; Y, R⁴ =H; R³ =O; and R⁵, R⁶ =Cl, or (l) X=o-F; Y, R⁴ =H; R³=S; and R⁵, R⁶ =Cl, or (m) X=o-F; Y, R⁴ =H; R³ =O; and R⁵ and R⁶together --(CH₂)₄ --, or (n) X=o-F; Y, R⁴, R⁶ =H; R⁵ =CF₃ ; and R³ =O,or (o) X=o-F; Y, R⁴, R⁶ =H; R⁵ =CF₃ ; and R³ =S, or (p) X=o-F; Y, R⁴, R⁶=H; R⁵ =Cl; R³ =O, or (q) X=o-F; Y, R⁴, R⁶ =H; R⁵ =Cl; and R³ =S.
 12. Acompound in accordance with claim 7, wherein R⁵ and R⁶, independently,are hydrogen, methyl, chlorine or methoxy.
 13. A compound in accordancewith claim 1 of the formula ##STR34## wherein X is hydrogen, fluorine,chlorine, lower alkoxy, lower alkyl or trifluromethyl; Y is hydrogen,fluorine, chlorine, lower alkoxy or lower alkyl; R⁵ and R⁶,independently, are hydrogen, methyl, fluorine, chlorine, methoxy ortrifluoromethyl, or taken together are --(CH₂)₄ --,its racemate, anenantiomer thereof, or a pharmaceutically acceptable acid addition saltthereof.
 14. A compound in accordance with claim 1 of the formula##STR35## wherein X is hydrogen, fluorine, chlorine, lower alkoxy, loweralkyl or trifluoromethyl; Y is hydrogen, fluorine, chlorine, loweralkoxy or lower alkyl; R² is lower alkyl, phenyl, phenyl substituted byhalogen, lower alkoxy or trifluoromethyl; and R⁷ is lower alkyl or loweralkanoyl, optionally substituted by halogen,its racemate, an enantiomerthereof, or a pharmaceutically acceptable acid addition salt thereof.15. A compound in accordance with claim 14, wherein X and Y arehydrogen, OR⁷ is β-orientated acetoxy and R² is n-butyl.
 16. A compoundin accordance with claim 14, wherein X and Y are hydrogen, OR⁷ isβ-orientated trifluroacetoxy and R² is tert.butyl.
 17. A compound inaccordance with claim 14, wherein X is o-chloro, OR⁷ is α-orientatedacetoxy and R² is phenyl.